Elucidating the role of CD26 in T cell-mediated tumor immunity

阐明 CD26 在 T 细胞介导的肿瘤免疫中的作用

基本信息

批准号：
9045382
负责人：
Stefanie Bailey
金额：
$ 4.36万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9045382
关键词：
Ablation Address Adoptive Cell Transfers Adoptive Immunotherapy Affect Affinity Antitumor Response CD4 Positive T Lymphocytes CD8B1 gene Cancer Patient Cell physiology Cell surface Cells Cellular biology Chemotaxis Clinic Clinical Clinical Trials Cytotoxin Data Dipeptides Engraftment Exhibits FDA approved Granzyme Growth Helper-Inducer T-Lymphocyte Human Human Activities Immune response Immunity Immunotherapy In Vitro Inflammatory Interferons Interleukin-17 Interleukin-2 Interleukin-6 Investigation Knowledge Life Macrophage Inflammatory Protein-1 Malignant Neoplasms Mediating Memory Mesothelioma Monophenol Monooxygenase Mus Pathway interactions Patients Phase I Clinical Trials Play Production Property RANTES Recruitment Activity Recurrence Reporting Research Role Sorting - Cell Movement Surface T memory cell T-Cell Receptor T-Lymphocyte Testing Therapeutic Time Translations Treatment outcome Tumor Immunity Vaccines base cancer immunotherapy cell motility chemokine clinically significant cytokine cytotoxic cytotoxicity design in vivo inhibitor/antagonist insight interleukin-22 interleukin-23 loss of function melanoma migration next generation novel programs public health relevance response tumor

项目摘要

DESCRIPTION (provided by applicant): Adoptive cell transfer (ACT) therapies for melanoma patients have failed to fulfill their therapeutic promise, largely due to the transfer of short-livd and terminally differentiated cells. A lack of means for developing long- lived T cell potency has hampered ACT advancement in the clinic. Understanding and manipulating the pathways that sustain T cell memory will potentially unlock durable responses to tumors. During my time in the Paulos lab, I have found that IL-17A/IFN-/IL-22-producing CD4+ T cells that express enzymatically active CD26 on their cell surface - termed CD4+CD26high T cells - demonstrate exquisite, durable responses to tumors compared to Th1 or Th17 cells. Further investigation revealed that these cells potentially induce the expansion and engraftment of cytotoxic CD8+ T cells in vivo. Interestingly, we found that abrogating the enzymatic activity of CD26 on CD4+CD26high T cells with Alogliptin dramatically impaired their capacity to secrete the pro-inflammatory cytokines IL-17A, IL-22, IFN- and IL-2, as well as the cytotoxin Granzyme B. Collectively, these data suggest that the enzymatic activity of CD26 plays a critical role in the function and cytotoxicity of CD4+CD26high T cells and could augment their antitumor properties in vivo. The importance of cytokine production by CD4+ T cells on the function, proliferation and cytotoxicity of CD8+ T cells has been well studied. Based on these reports, the loss of function induced by the inhibition of CD26 enzymatic activity could potentially reduce the ability of CD4+CD26high T cells to support CD8+ T cells. Given that the combined transfer of CD4+ and CD8+ T cells has proven efficacious in ACT therapy, it's important to deduce how the enzymatic activity of CD26 on CD4+CD26high T cells affects CD8+ T cells and if this activity can be targeted for enhanced therapy. We propose to gain further insight into CD4+CD26high T cell-mediated tumor immunity, hypothesizing that the enzymatic activity of CD26 plays a crucial role in the overall activity of human CD4+CD26highT cells as well as their ability to support CD8+ T cells (Aim 1), and that targeting this novel pathway is crucial for prolonging the efficacy of cancer immunotherapy (Aim 2). Overall, the proposed research is expected to demonstrate that manipulation of the CD26 pathway may sufficiently induce durable immunity against the growth and recurrence of advanced melanoma.

描述（由申请人提供）：针对黑色素瘤患者的过继性细胞移植（ACT）疗法未能实现其治疗承诺，这主要是由于短寿命和终末分化细胞的移植缺乏开发长寿命 T 细胞的方法。在 Paulos 实验室期间，我发现理解和操纵维持 T 细胞记忆的途径可能会释放对肿瘤的持久反应。进一步研究表明，与 Th1 或 Th17 细胞相比，产生 IL-17A/IFN-γ/IL-22 的 CD4+ T 细胞（称为 CD4+CD26high T 细胞）对肿瘤具有精细、持久的反应，这些细胞表面表达酶活性 CD26。这些细胞可能在体内诱导细胞毒性 CD8+ T 细胞的扩增和植入，我们发现消除 CD26 的酶活性。使用阿格列汀的 CD4+CD26high T 细胞会显着削弱其分泌促炎细胞因子 IL-17A、IL-22、IFN-γ 和 IL-2 以及细胞毒素颗粒酶 B 的能力。总的来说，这些数据表明， CD26 的活性在 CD4+CD26high T 细胞的功能和细胞毒性中起着至关重要的作用，并且可以增强其体内抗肿瘤特性 CD4+ 产生细胞因子的重要性。 T 细胞对 CD8+ T 细胞的功能、增殖和细胞毒性已得到充分研究，基于这些报告，CD26 酶活性抑制引起的功能丧失可能会降低 CD4+CD26high T 细胞支持 CD8+ T 的能力。鉴于 CD4+ 和 CD8+ T 细胞的联合转移已被证明在 ACT 治疗中有效，因此推断 CD26 对 CD4+CD26high T 细胞的酶活性如何非常重要。细胞影响 CD8+ T 细胞，如果这种活性可以作为增强治疗的目标，我们建议进一步了解 CD4+CD26 高 T 细胞介导的肿瘤免疫，假设 CD26 的酶活性在人类的整体活性中起着至关重要的作用。 CD4+CD26highT 细胞及其支持 CD8+T 细胞的能力（目标 1），而针对这一新途径对于延长癌症免疫疗法的疗效至关重要（目标 2）。拟议的研究预计将证明对 CD26 通路的操纵可能足以诱导针对晚期黑色素瘤生长和复发的持久免疫力。